Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphé Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning

Abstract

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid, in the OFC. Additionally, 5-HT 2A receptor binding in the OFC of mid-and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low-vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.

Perseveration in a spatial-discrimination serial reversal learning task is differentially affected by MAO-A and MAO-B inhibition and associated with reduced anxiety and peripheral serotonin levels

“…Errors were considered perseverative in nature if in a window of 10 trials, 7 incorrect responses were made. The number of perseverative errors made during the three reversals was used to rank the animals, consistent with (Barlow et al 2015). Based on this ranking, three groups were formed that included highly perseverative ( n  = 11), mid-range ( n  = 20), and low-perseverative animals ( n  = 11).…”

Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder

“…OFC 5HT depletion studies in marmosets and rats have indicated impairments in serial visual reversal learning [45, 97, 98], detour-reaching task [46] as well as attentional set-shifting task [99]. Likewise, 5HT markers in the rodent OFC have been shown to correlate with performances on a spatial reversal learning task while its reuptake inhibitor, citalopram was shown to improve performance [100]. In contrast, OFC specific administration of a 5-HT 2C antagonist significantly enhanced performance on different reversal learning based tasks [101–103].…”

The neural basis of reversal learning: An updated perspective

“…For example, rats systemically treated with para-chloroamphetamine (PCA) or parachlorophenylalanine (PCPA), both of which produce significant depletion of brain serotonin, showed impaired stimulus-reward, discrimination and reversal learning (Masaki et al, 2006, Izquierdo et al, 2012). However, serotonin and serotonin transporter levels in the rodent OFC predict individual variation in reversal learning performance, suggesting a more circumscribed role for the transmitter (Stolyarova et al, 2014, Barlow et al, 2015). A study in vervet monkeys by Groman and colleagues also reported that serotonin levels in ventrolateral PFC/Area 47 correlated with reversal learning performance (Groman et al, 2013).…”